Project Summary The molecular pathways underlying cognition and vocal communication remain largely unknown. The genes and mechanisms governing these processes are disrupted in many neurodevelopmental disorders, including intellectual disability and autism spectrum disorder. The long-term goal of our laboratory is to study the normal function of genes disrupted in disorders with deficits in cognition, communication, and social behavior, to gain mechanistic understanding that can be leveraged for treatment opportunities. Mutations in the gene encoding the ubiquitin ligase UBE3B have been identified in patients with intellectual disability and lack of speech. The specific mechanism(s) that give rise to the neurodevelopmental phenotypes and the UBE3B substrates that mediate these mechanisms are completely unknown. Our preliminary studies suggest a role for UBE3B in brain development and vocalization. In addition, we identified the branched-chain a-ketoacid dehydrogenase kinase (BCKDK) as a substrate for UBE3B. We propose to dissect the molecular networks regulated by UBE3B and its role in mediating vocalization, through the following three specific aims: 1) Determine the role of UBE3B in vocalization; 2) Identify the neuronal substrates of UBE3B through quantitative proteomics and biochemical validation experiments; 3) Rescue the neurodevelopmental phenotypes associated with UBE3B loss of function by targeting its substrate BCKDK. Together, these aims will identify the molecular networks regulated by UBE3B that may underlie the lack of speech and other neurodevelopmental phenotypes observed in patients with UBE3B disruption. Successful completion of the proposed aims will provide new insights into pathways regulating vocalization, increase our knowledge of the specific pathogenic mechanism underlying neurodevelopmental disorders with communication deficits, and examine new therapeutic approaches.